EP0723959A1 - Heterocyclic compounds as tachykinin receptor antagonists, process for their preparation and pharmaceuticals containing them - Google Patents

Abstract

4-Aryl-4-(cyclic aminoalkyl)- 1-benzyl-2-pyrrolidone derivs. (including piperidinone and perhydroazepinone analogues) of formula (I) and their mineral or organic acid addn. salts and solvates are new. m = 2 or 3; n = 0-2; Am = substd. piperidino or quinuclidino gp. of formula (a) or (b) or, if n = 0, can also be substd. piperidino of formula (c); R1 = 1-4C alkyl or benzyl; R2 = phenyl opt. substd. by one or more of halo, OH, 1-4C alkyl, 1-4C alkoxy and CF3; X = H or OH; x = 0 or 1; Ar = phenyl opt. substd. by one or more halo; naphthyl; or indolyl; Z = phenyl opt. substd. by one or more of halo, 1-4C alkyl and CF3; and A<-> = anion.

Description

The present invention relates to new heterocyclic compounds, a process for their preparation and the pharmaceutical compositions containing them as active ingredient.

More particularly, the present invention relates to a new class of aromatic compounds for therapeutic use, in pathological phenomena which involve the tachykinin system such as for example in a nonlimiting and exclusive manner: pain (D. Regoli et al., Life Sciences, 1987, 40 , 109-117), allergy and inflammation (JE Morlay et al., Life Sciences, 1987, 41 , 527-544), circulatory failure (J. Losay et al., 1977, Substance P, Von Euler, IS and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6 , 481-484), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50) neurological disorders, neuropsychiatric disorders.

In recent years, much research has been done on tachykinins and their receptors. Tachykinins are distributed in both the central nervous system and the peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK ₁ , NK ₂ , NK ₃ . Substance P (SP) is the endogenous ligand for NK ₁ receptors, neurokinin A (NK _A ) for NK ₂ receptors and neurokinin B (NK _B ) for NK ₃ receptors.

The NK ₁ , NK ₂ , NK ₃ receptors have been demonstrated in different species. A review by CA Maggi et al. takes stock of tachykinin receptors and their antagonists and describes pharmacological studies and applications in human therapy (J. Autonomic Pharmacol., 1993, 13 , 23-93).

Among the specific antagonists of the NK ₁ receptor, the following non-peptide compounds may be mentioned: CP-96345 (J. Med. Chem., 1992, 35 , 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA , 1991, 88 , 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

dans laquelle notamment :

• Q' représente un atome d'oxygène ou deux atomes d'hydrogène,
• T' = -C(O)- ou -CH₂-, et
• Y peut représenter un groupe
  
  dans lequel
  • Ar' représente un phényle éventuellement substitué,
  • x'= 0 ou 1 et
  • X' représente l'hydrogène, un groupe hydroxyle ou un autre radical monovalent, ainsi que les sels d'ammonium quaternaire avec l'azote de la pipéridine.

Cette demande de brevet ne décrit aucun composé de formule 1 dans laquelle à la fois: Q' est l'oxygène et Y représente un groupe 4-phénylpipéridine ou 4-benzylpipéridine qui soit sous forme de sel d'ammonium quaternaire avec l'azote de la pipéridine, ni aucun composé de formule 1 dans laquelle à la fois : Q' est l'oxygène, n'=p'=1, Y représente un groupe 4-phénylpipéridine ou 4-benzylpipéridine ou 4-hydroxy-4-phénylpipéridine ou 4-hydroxy-4-benzylpipéridine et -T-(CH₂)_q-Z' représente un benzyle substitué.Many patents or patent applications describe compounds active on the tachykinin receptors. Thus, European patent application 0 512 901 relates to compounds of formula:

in which in particular:

• Q 'represents an oxygen atom or two hydrogen atoms,
• T '= -C (O) - or -CH ₂ -, and
• Y can represent a group
  
  in which
  • Ar 'represents an optionally substituted phenyl,
  • x '= 0 or 1 and
  • X 'represents hydrogen, a hydroxyl group or another monovalent radical, as well as the quaternary ammonium salts with the nitrogen of piperidine.

This patent application does not describe any compound of formula 1 in which both: Q 'is oxygen and Y represents a 4-phenylpiperidine or 4-benzylpiperidine group which is in the form of quaternary ammonium salt with nitrogen from piperidine, or any compound of formula 1 in which at the same time: Q 'is oxygen, n' = p '= 1, Y represents a 4-phenylpiperidine or 4-benzylpiperidine or 4-hydroxy-4-phenylpiperidine group or 4-hydroxy-4-benzylpiperidine and -T- (CH ₂ ) _q -Z 'represents a substituted benzyl.

dans laquelle notamment :

• Ar₁ représente un groupe aromatique ou hétéroaromatique mono-, di- ou tricyclique éventuellement substitué;
• T₁ représente une liaison directe, un groupe hydroxyméthylène, alcoxyméthylène ou alkylène ;
• Ar'₁ représente un phényle non substitué ou substitué ; un thiényle ; un benzothiényle; un naphtyle ou un indolyle ;
• Am^⊕ ₁ représente le radical
  
  dans lequel X₁, X₂, X₃ ensemble avec l'atome d'azote auquel ils sont liés, forment un système azabicyclique ou azatricyclique, par exemple le groupe 4-phényl-1-azoniabicyclo[2.2.2]octane;
• R'₁ a différentes significations ou représente l'hydrogène ;
• Q'₁ représente l'hydrogène ou
• Q'₁ et R'₁ ensemble forment un groupe 1,2-éthylène, 1,3-propylène ou 1,4-butylène.

European patent application 0 591 040 relates to compounds of formula:

in which in particular:

• Ar ₁ represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
• T ₁ represents a direct bond, a hydroxymethylene, alkoxymethylene or alkylene group;
• Ar ' ₁ represents an unsubstituted or substituted phenyl; thienyl; benzothienyl; naphthyl or indolyl;
• Am ^⊕ ₁ represents the radical
  
  in which X ₁ , X ₂ , X ₃ together with the nitrogen atom to which they are linked, form an azabicyclic or azatricyclic system, for example the group 4-phenyl-1-azoniabicyclo [2.2.2] octane;
• R ' ₁ has different meanings or represents hydrogen;
• Q ' ₁ represents hydrogen or
• Q ' ₁ and R' ₁ together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group.

We have now found non-peptide compounds which have a very high affinity for the NK ₁ receptor and a high specificity for said receptor. These compounds can be used for the preparation of medicaments useful in the treatment of any P-dependent substance pathology.

By very strong affinity for the human NK ₁ receptor is meant an affinity characterized by an inhibition constant Ki of less than 5.10 ^-9 M.

[L] : concentration du ligand,
Kd : constante de dissociation du ligand,
IC₅₀ : concentration qui inhibe 50 % de la fixation du ligand.In ligand binding studies, the inhibition constant Ki is defined by the Cheng-Prusoff relationship (in Receptor Binding in Drug Research, eds. RA O'Brien, Marcel Dekker, New York, 1986): $$\text{Ki =}\frac{{\text{IC}}_{\text{50}}}{\text{1 +}\frac{\left[\text{L}\right]}{\text{Kd}}}$$

[L]: concentration of ligand,
Kd: ligand dissociation constant,
IC ₅₀ : concentration which inhibits 50% of ligand binding.

By high specificity for the human NK ₁ receptor, it is meant that the inhibition constant (Ki) for the human NK ₁ receptor is at least 100 times lower than the inhibition constant (Ki) for the NK ₂ receptor or that for the NK ₃ receiver.

dans laquelle

• m est deux ou trois ;
• n est 0, 1 ou 2 ;
• Am représente un groupe choisi parmi :
  • a)
    
    b)
    
    et lorsque n = 0, Am peut également représenter le groupe :
  • c)
    
    • R₁ représente un (C₁-C₄)alkyle ou un benzyle ;
    • R₂ représente un phényle non substitué ou substitué une ou plusieurs fois par un atome d'halogène, un hydroxyle, un (C₁-C₄)alcoxy, un (C₁-C₄)alkyle, un trifluorométhyle, lesdits substituants étant identiques ou différents ;
    • X représente un atome d'hydrogène ou un groupe hydroxyle ;
    • x est zéro ou un ;
    • Ar représente un phényle non substitué ou substitué une ou plusieurs fois par un atome d'halogène ; un naphtyle ou un indolyle ;
    • Z représente un phényle substitué une ou plusieurs fois par un atome d'halogène, un (C₁-C₄) alkyle, un trifluorométhyle ;
    • A^⊖ représente un anion ;
    ainsi que leurs sels éventuels avec des acides minéraux ou organiques et leurs solvates éventuels.
  
  Les composés de formule (I) selon l'invention comprennent aussi bien les isomères optiquement purs que les racémiques ainsi que les isomères axiaux et équatoriaux lorsque Am a la valeur a).
  Lorsque Am représente c), on peut former des sels des composés de formule (I). Ces sels comprennent aussi bien ceux des acides minéraux ou organiques qui permettent une séparation ou une cristallisation convenable des composés de formule (I), tels que l'acide picrique oxalique ou un acide optiquement actif, par exemple un acide mandélique ou camphosulfonique, que ceux qui forment des sels pharmaceutiquement acceptables tels que le chlorhydrate, le bromhydrate, le sulfate, l'hydrogénosulfate, le dihydrogénophosphate, le méthanesulfonate, le méthylsulfate, le maléate, le fumarate, le 2-naphtalènesulfonate, le benzènesulfonate, le gluconate, le citrate, l'iséthionate, le p-toluènesulfonate.
  Les anions sont ceux normalement utilisés pour salifier les ions d'ammonium quaternaires, de préférence les ions chlorure, bromure, iodure, acétate, hydrogénosulfate, méthanesulfonate, paratoluènesulfonate, benzènesulfonate.
  Préférentiellement, on utilise les anions pharmaceutiquement acceptables par exemple le chlorure, le méthanesulfonate, le paratoluènesulfonate, le benzènesulfonate.
  Dans la présente description les groupes alkyles ou les groupes alcoxy sont droits ou ramifiés ; par atome d'halogène on entend un atome de chlore, de brome, de fluor ou d'iode.
  Avantageusement, la présente invention concerne les composés de formule (I) dans laquelle m = 2.
  Les composés de formule (I) dans lesquels Z est un groupe choisi parmi diméthylphényle, trifluorométhylphényle et bistrifluorométhylphényle sont des composés préférés selon l'invention.
  Selon la présente invention, on préfère les composés de formule (I) dans laquelle
  • Ar représente un 3,4-dichlorophényle ou un 3,4-difluorophényle ;
  • Z représente un 3,5-diméthylphényle, un 3,5-bis(trifluorométhyl)phényle ou un 2,4-bis(trifluorométhyl)phényle ;
  • et soit n = 0, 1 ou 2 et Am représente a) ou b), - soit n = 0 et Am représente c) ;
  • A^⊖ représente un anion pharmaceutiquement acceptable.
  
  Selon la présente invention, on préfère également les composés de formule :
  
  dans laquelle Am_a représente le groupe b) tel que défini pour (I) et n, m, Ar et Z sont tels que définis pour (I) et leurs solvates éventuels.
  Tout particulièrement, on préfère les sels pharmaceutiquement acceptables des composés de formule :
  
  dans laquelle a est 0 ou 1 ;
  et leurs solvates éventuels.
  Selon un autre de ses aspects, la présente invention concerne un procédé pour la préparation des composés de formule (I) caractérisé en ce que :
  • 1) on traite un composé de formule :
    
    dans laquelle m, n et Ar sont tels que définis pour (I) et E représente un groupe O-protecteur tel que le tétrahydropyran-2-yle, le benzoyle ou un acyle en C₁-C₄ ;
    avec un dérivé halogéné de formule :
    
            Hal-CH₂-Z     (III)
    
    dans laquelle Z est tel que défini pour (I) et Hal représente un atome d'halogène, préférentiellement le brome ou le chlore ;
  • 2) on transforme le groupe O-protecteur en groupe hydroxyle par action d'un acide ou d'une base ;
  • 3) on traite l'alcool ainsi obtenu de formule :
    
    dans laquelle Ar, Z, m et n sont tels que définis précédemment avec le chlorure de méthanesulfonyle, le chlorure de benzènesulfonyle, le chlorure de paratoluènesulfonyle ou le chlorure de trifluorométhanesulfonyle;
  • 4) on fait réagir le composé ainsi obtenu de formule :
    
    dans laquelle R représente un groupe méthyle, phényle, paratolyle ou trifluorométhyle ;
    avec une amine secondaire ou tertiaire AmH ou Am dans un solvant organique, à une température comprise entre la température ambiante et 120°C ;
  • 5) on isole le produit ainsi obtenu et, éventuellement, on échange l'anion sulfonate avec un autre anion, et, éventuellement, on transforme le produit ainsi obtenu en un de ses sels.
  
  A l'étape 2, la déprotection est effectuée en milieu acide, par exemple en présence d'acide chlorhydrique lorsque E représente un tétrahydropyran-2-yle ou en milieu basique, par exemple en présence de soude ou d'hydroxyde de lithium lorsque E représente un benzoyle ou un acyle en C₁-C₄.
  A la dernière étape l'anion sulfonate peut être échangé, in situ ou après isolement du composé de formule (I) dans laquelle A^⊖ est l'ion sulfonate, par un autre anion A^⊖, selon les méthodes conventionnelles, par exemple par échange en solution avec une solution saturée de chlorure de sodium ou, avec une solution d'acide chlorhydrique lorsque A^⊖ représente un anion chlorure, ou par échange de l'anion par élution du composé (I) sur une résine échangeuse d'ion, par exemple l'Amberlite IRA68 ou Duolite A375.
  Lorsque Am représente un groupe a), les sels d'ammonium quaternaires formés avec l'azote de la pipéridine sont préparés par réaction des bases libres des composés de formule (I) avec un excès d'agent alkylant de formule : A-R₁ dans lequel A est tel que défini précédemment pour (I), de préférence un chlorure ou un iodure et R₁ est tel que défini précédemment pour (I) et on chauffe le mélange réactionnel dans un solvant, par exemple le dichlorométhane, le chloroforme, l'acétone ou l'acétonitrile, à une température comprise entre la température ambiante et le reflux, pendant une à plusieurs heures, pour obtenir après traitement selon les méthodes habituelles un mélange des isomères axiaux et équatoriaux des sels d'ammonium quaternaires. De préférence, A^⊖ représente un iodure qui peut être échangé par un autre anion ou par un anion pharmaceutiquement acceptable, par exemple par élution du composé (I) sur une résine échangeuse d'ion, telle l'Amberlite IRA68 ou Duolite A375. Les isomères sont séparés selon les méthodes habituelles, par exemple par chromatographie ou par recristallisation.
  La résolution des mélanges racémiques de composés (I) ou d'intermédiaires tels que (IV) permet d'isoler les énantiomères en utilisant des méthodes connues de l'homme de l'art.
  La préparation des composés de formule (II) est effectuée selon les procédés décrits dans EP-A-0 512 901.
  Les dérivés halogénés de formule (III) sont connus ou préparés par des méthodes connues.
  La 4-phénylpipéridine, la 4-benzylpipéridine, la 4-hydroxy-4-phénylpipéridine et la 4-hydroxy-4-benzylpipéridine sont commerciales.
  La 4-phényl-1-wabicyclo[2.2.2]octane, ou 4-phénylquinuclidine et la 4-benzyl-1-azabicyclo[2.2.2]octane ou 4-benzylquinuclidine sont préparées selon T. Perrine, J. Org. Chem., 1957, 22, 1484-1489.
  Les composés de formule (I) ci-dessus comprennent également ceux dans lesquels un ou plusieurs atomes d'hydrogène, de carbone, de fluor ou d'iode ont été remplacés par leur isotope radioactif par exemple le tritium, le carbone-14, le fluor-19 ou l'iode 125. De tels composés marqués sont utiles dans des travaux de recherche, de métabolisme, de pharmacocinétique ou dans des essais biochimiques en tant que ligands de récepteurs et peuvent être utilisés comme outils pharmacologiques chez l'homme ou chez l'animal.
  Les composés selon l'invention ont fait l'objet d'essais biochimiques.
  L'affinité des composés de formule (I) pour les récepteurs aux tachykinines a été évaluée in vitro par plusieurs essais biochimiques utilisant des radioligands :
  • 1°) La liaison de [¹²⁵I]BH-SP (Substance P marquée à l'iode 125 à l'aide du réactif de Bolton-Hunter) aux récepteurs NK₁ des cellules lymphoblastiques humaines.
  • 2°) La liaison [¹²⁵I]His-NK_A aux récepteurs NK₂ du duodénum ou de la vessie de rat.
  • 3°) La liaison [¹²⁵I]His[MePhe⁷]NK_B aux récepteurs NK₃ du cortex cérébral de rat, du cortex cérébral de cobaye et du cortex cérébral de gerbille ainsi qu'aux récepteurs clones NK₃ humains exprimés par des cellules CHO (Buell et al., FEBS Letters, 1992, 299, 90-95).
  
  Les essais ont été effectués selon X. Emonds-Alt et al. (Eur. J. Pharmacol., 1993, 250, 403-413).
  Les composés selon l'invention inhibent fortement la liaison aux récepteurs NK₁ des cellules lymphoblastiques humaines IM9. la constante d'inhibition Ki pour les récepteurs des cellules lymphoblastiques est inférieure à 5.10^-9M. Pour les mêmes composés on a constaté que la constante d'inhibition (Ki) pour les récepteurs NK₃ clonés humains est supérieure ou égale à 10^-7M et que la constante d'inhibition (Ki) pour le récepteur NK₂ du duodénum ou de la vessie de rat est supérieure ou égale à 10^-7M.
  L'activité des composés selon la présente invention comme inhibiteurs de la liaison aux récepteurs NK₁ est nettement supérieure à celle de composés voisins décrits dans l'art antérieur.
  Ainsi, l'isomère axial de l'iodure de 1-méthyl-1-[2-[1-[3,5-bis(trifluorométhyl) benzyl]-5-(3,4-dichlorophényl)-2-oxopipérid-5-yl]éthyl]-4-phénylpipéridinium présente une constante d'inhibition Ki de la substance P au récepteur lymphoblastique humain de l'ordre de 0,1.10^-9M alors que le chlorhydrate de 5-[2-(4-benzyl-1-pipérid-1-yl)éthyl]-5-(3,4-dichlorophényl)-1-benzylpipérid-2-one décrit dans la demande EP-0 512 901 à l'exemple 1 (composé non substitué sur le benzyle) présente une constante d'inhibition Ki de l'ordre de 10^-6M mesurée dans les mêmes conditions.
  De même le chlorhydrate de 4-(3,4-dichlorophényl)-4-[2-(4-hydroxy-4-phénylpipérid-1-yl)éthyl]-1-[3,5-bis(trifluorométhyl)benzyl]pyrrolidin-2-one présente une constante d'inhibition Ki de la substance P au récepteur lymphoblastique humain de l'ordre de 0,1.10^-9M alors que le chlorhydrate de 1-benzyl-4-(3,4-dichlorophényl)-4-[2-(4-hydroxy-4-phénylpipérid-1-yl)éthyl]pipérid-2-one décrit dans la demande EP-0 512 901 à l'exemple 3 présente un Ki de l'ordre de 10^-6M mesuré dans les mêmes conditions.
  Les composés de la présente invention sont notamment des principes actifs de compositions pharmaceutiques, dont la toxicité est compatible avec leur utilisation en tant que médicaments.
  Les composés de formule (I) ci-dessus peuvent être utilisés à des doses journalières de 0,01 à 100 mg par kilo de poids corporel du mammifère à traiter, de préférence à des doses journalières de 0,1 à 50 mg/kg. Chez l'être humain, la dose peut varier de préférence de 0,5 à 4000 mg par jour, plus particulièrement de 2,5 à 1000 mg par jour selon l'âge du sujet à traiter ou le type de traitement : prophylactique ou curatif.
  Pour leur utilisation comme médicaments, les composés de formule (I) sont généralement administrés en unités de dosage. Lesdites unités de dosage sont de préférence formulées dans des compositions pharmaceutiques dans lesquelles le principe actif est mélangé avec un excipient pharmaceutique.
  Ainsi, selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques renfermant, en tant que principe actif, un composé de formule (I).
  Dans les compositions pharmaceutiques de la présente invention pour l'administration par voie orale, sublinguale, inhalée, sous-cutanée, intramusculaire, intraveineuse, transdermique, locale ou rectale, les principes actifs peuvent être administrés sous formes unitaires d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les aérosols, les implants, les formes d'administration sous-cutanée, intramusculaire, intraveineuse, intranasale ou intraoculaire et les formes d'administration rectale.
  Lorsque l'on prépare une composition solide sous forme de comprimés, on mélange le principe actif principal avec un véhicule pharmaceutique tel que la silice, la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique ou analogues. On peut enrober les comprimés de saccharose de divers polymères, ou d'autres matières appropriées ou encore les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif.
  On obtient une préparation en gélules en mélangeant le principe actif avec un diluant tel qu'un glycol ou un ester de glycérol et en incorporant le mélange obtenu dans des gélules molles ou dures.
  Une préparation sous forme de sirop ou d'élixir peut contenir le principe actif conjointement avec un édulcorant, acalorique de préférence, du méthylparaben et du propylparaben comme antiseptique, ainsi qu'un agent donnant du goût et un colorant approprié.
  Les poudres ou les granules dispersibles dans l'eau peuvent contenir le principe actif en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, comme la polyvinylpyrrolidone, de même qu'avec des édulcorants ou des correcteurs du goût.
  Pour une administration rectale, on recourt à des suppositoires qui sont préparés avec des liants fondant à la température rectale, par exemple du beurre de cacao ou des polyéthylèneglycols.
  Pour une administration parentérale, intranasale ou intraoculaire, on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des agents mouillants pharmacologiquement compatibles, par exemple le propylèneglycol ou le butylèneglycol.
  Pour une administration par inhalation, on utilise un aérosol contenant par exemple du trioléate de sorbitane ou de l'acide oléique ainsi que du trichlorofluorométhane, du dichlorofluorométhane, du dichlorotétrafluoroéthane ou tout autre gaz propulseur biologiquement compatible ; on peut également utiliser un système comprenant le principe actif, seul ou associé à un excipient, sous forme de poudre.
  Le principe actif peut être formulé également sous forme de microcapsules, éventuellement avec un ou plusieurs supports ou additifs.
  Dans chaque unité de dosage le principe actif de formule (I) est présent dans les quantités adaptées aux doses journalières envisagées. En général chaque unité de dosage est convenablement ajustée selon le dosage et le type d'administration prévu, par exemple comprimés, gélules et similaires, sachets, ampoules, sirops et similaires, gouttes de façon à ce qu'une telle unité de dosage contienne de 0,5 à 1000 mg de principe actif, de préférence de 2,5 à 250 mg, devant être administrée une a quatre fois par jour.
  Selon un autre de ses aspects, la présente invention concerne l'utilisation des produits de formule (I) pour la préparation de médicaments destinés à traiter des troubles physiologiques associés à un excès de tachykinines, notamment de Substance P et toutes les pathologies Substance-P-dépendantes du système respiratoire, gastro-intestinal, urinaire, immunitaire, cardiovasculaire et du système nerveux central ainsi que la douleur et la migraine.
  Par exemple et de manière non limitative :
  • douleurs aigües et chroniques liées par exemple à la migraine, aux douleurs du cancéreux et de l'angineux, aux processus inflammatoires chroniques tels que l'ostéoarthrite et l'arthrite rhumatoïde,
  • les inflammations telles que les maladies respiratoires chroniques obstructives, l'asthme, les allergies, les rhinites, les toux, les bronchites, l'hypersensibilité par exemple aux pollens et aux acariens, les arthrites rhumatoïdes, les ostéoarthrites, le psoriasis, les colites ulcératives, la maladie de Crohn, l'inflammation des intestins (colon irritable), la prostatite, la vessie neurologique, la cystite, l'urétrite, la néphrite,
  • les maladies du système immunitaire liées à la suppression ou à la stimulation des fonctions des cellules immunes par exemple l'arthrite rhumatoïde, le psoriasis, la maladie de Crohn, la diabète, le lupus,
  • les maladies du système nerveux central du type neuropsychiatrique ou neurologique telles que l'anxiété, la dépression, la psychose, la schizophrénie, la manie, la démence, l'épilepsie, la maladie de Parkinson, la maladie d'Alzheimer, la drogue-dépendance, le syndrome de Down et la chorée d'Huntington ainsi que les maladies neurodégénératives,
  • les maladies du système gastro-intestinal telles que nausées, vomissement, colon irritable, ulcères gastriques et duodénaux, diarrhées, hypersécrétions,
  • les maladies du système cardiovasculaire telles que les l'hypertension, les aspects vasculaires de la migraine, oedèmes, thrombose, l'angine de poitrine et les spasmes vasculaires,
  • les troubles de la fréquence et du rythme cardiaques, en particulier ceux qui sont occasionnés par la douleur ou le stress.
  
  La présente invention inclut aussi une méthode pour traiter lesdites affections aux doses indiquées ci-dessus.
  Dans les Préparations et dans les exemples on utilise les abréviations suivantes :
  EtOH : éthanol
  MeOH : méthanol
  Ether : éther diéthylique
  Ether iso : éther diisopropylique
  DMF : diméthylformamide
  AcOEt : acétate d'éthyle
  DCM : dichlorométhane
  THF: tétrahydrofurane
  NaOH : soude
  KHCO₃ : hydrogénocarbonate de potassium
  NaHCO₃ : hydrogénocarbonate de sodium
  NaCl : chlorure de sodium
  Triton B : solution à 40 % d'hydroxyde de N-benzyltriméthylammonium dans le MeOH.
  Na₂SO₄ : sulfate de sodium
  MgSO₄ : sulfate de magnésium
  iPr: isopropyle
  TA : température ambiante
  F : point de fusion
  RMN : résonnance magnétique nucléaire.
  s : singulet
  sd : singulet dédoublé
  d : doublet
  sept : septuplet
  m : massif
  mult : multiplet

Thus according to one of its aspects, the present invention relates to compounds of formula:

in which

• m is two or three;
• n is 0, 1 or 2;
• Am represents a group chosen from:
  • at)
    
    b)
    
    and when n = 0, Am can also represent the group:
  • vs)
    
    • R ₁ represents a (C ₁ -C ₄ ) alkyl or a benzyl;
    • R ₂ represents a phenyl which is unsubstituted or substituted one or more times by a halogen atom, a hydroxyl, a (C ₁ -C ₄ ) alkoxy, a (C ₁ -C ₄ ) alkyl, a trifluoromethyl, said substituents being identical or different;
    • X represents a hydrogen atom or a hydroxyl group;
    • x is zero or one;
    • Ar represents phenyl which is unsubstituted or substituted one or more times by a halogen atom; naphthyl or indolyl;
    • Z represents a phenyl substituted one or more times by a halogen atom, a (C ₁ -C ₄ ) alkyl, a trifluoromethyl;
    • A ^⊖ represents an anion;
    as well as their possible salts with mineral or organic acids and their possible solvates.
  
  The compounds of formula (I) according to the invention include both the optically pure isomers and the racemates as well as the axial and equatorial isomers when Am has the value a).
  When Am represents c), salts of the compounds of formula (I) can be formed. These salts include both those of mineral or organic acids which allow suitable separation or crystallization of the compounds of formula (I), such as picric oxalic acid or an optically active acid, for example a mandelic or camphosulfonic acid, as those which form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methanesulfonate, the methyl sulfate, the maleate, the fumarate, the 2-naphthalenesulfonate, the benzenesulfonate, the gluconate, the citrate, isethionate, p -toluenesulfonate.
  The anions are those normally used to salify the quaternary ammonium ions, preferably the chloride, bromide, iodide, acetate, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, benzenesulfonate ions.
  Preferably, the pharmaceutically acceptable anions are used, for example chloride, methanesulfonate, paratoluenesulfonate, benzenesulfonate.
  In the present description, the alkyl groups or the alkoxy groups are straight or branched; halogen atom means a chlorine, bromine, fluorine or iodine atom.
  Advantageously, the present invention relates to the compounds of formula (I) in which m = 2.
  The compounds of formula (I) in which Z is a group chosen from dimethylphenyl, trifluoromethylphenyl and bistrifluoromethylphenyl are preferred compounds according to the invention.
  According to the present invention, the compounds of formula (I) are preferred in which
  • Ar represents 3,4-dichlorophenyl or 3,4-difluorophenyl;
  • Z represents 3,5-dimethylphenyl, 3,5-bis (trifluoromethyl) phenyl or 2,4-bis (trifluoromethyl) phenyl;
  • and either n = 0, 1 or 2 and Am represents a) or b), - or n = 0 and Am represents c);
  • A ^⊖ represents a pharmaceutically acceptable anion.
  
  According to the present invention, the compounds of formula:
  
  in which Am _a represents group b) as defined for (I) and n, m, Ar and Z are as defined for (I) and their optional solvates.
  Most particularly, the pharmaceutically acceptable salts of the compounds of formula:
  
  where a is 0 or 1;
  and their possible solvates.
  According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I) characterized in that:
  • 1) a compound of formula is treated:
    
    in which m, n and Ar are as defined for (I) and E represents an O-protecting group such as tetrahydropyran-2-yl, benzoyl or a C ₁ -C ₄ acyl;
    with a halogenated derivative of formula:
    
    Hal-CH ₂ -Z (III)
    
    wherein Z is as defined for (I) and Hal represents a halogen atom, preferably bromine or chlorine;
  • 2) the O-protecting group is transformed into a hydroxyl group by the action of an acid or a base;
  • 3) the alcohol thus obtained is treated with the formula:
    
    in which Ar, Z, m and n are as defined above with methanesulfonyl chloride, benzenesulfonyl chloride, paratoluenesulfonyl chloride or trifluoromethanesulfonyl chloride;
  • 4) reacting the compound thus obtained of formula:
    
    wherein R represents a methyl, phenyl, paratolyl or trifluoromethyl group;
    with a secondary or tertiary amine AmH or Am in an organic solvent, at a temperature between room temperature and 120 ° C;
  • 5) the product thus obtained is isolated and, optionally, the sulfonate anion is exchanged with another anion, and, optionally, the product thus obtained is transformed into one of its salts.
  
  In step 2, the deprotection is carried out in an acid medium, for example in the presence of hydrochloric acid when E represents a tetrahydropyran-2-yl or in a basic medium, for example in the presence of sodium hydroxide or hydroxide when E represents a benzoyl or a C ₁ -C ₄ acyl.
  At the last step the sulfonate anion can be exchanged, in situ or after isolation of the compound of formula (I) in which A ^⊖ is the sulfonate ion, by another anion A ^⊖ , according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or, with a hydrochloric acid solution when A ^⊖ represents a chloride anion, or by exchange of the anion by elution of the compound (I) on an ion exchange resin, by example the Amberlite IRA68 or Duolite A375.
  When Am represents a group a), the quaternary ammonium salts formed with the piperidine nitrogen are prepared by reaction of the free bases of the compounds of formula (I) with an excess of alkylating agent of formula: AR ₁ in which A is as defined above for (I), preferably a chloride or an iodide and R ₁ is as defined above for (I) and the reaction mixture is heated in a solvent, for example dichloromethane, chloroform, acetone or acetonitrile, at a temperature between room temperature and reflux, for one to several hours, to obtain, after treatment according to the usual methods, a mixture of the axial and equatorial isomers of the quaternary ammonium salts. Preferably, A ^⊖ represents an iodide which can be exchanged with another anion or with a pharmaceutically acceptable anion, for example by elution of the compound (I) on an ion exchange resin, such as Amberlite IRA68 or Duolite A375. The isomers are separated according to the usual methods, for example by chromatography or by recrystallization.
  The resolution of racemic mixtures of compounds (I) or intermediates such as (IV) makes it possible to isolate the enantiomers using methods known to those skilled in the art.
  The preparation of the compounds of formula (II) is carried out according to the methods described in EP-A-0 512 901.
  The halogenated derivatives of formula (III) are known or are prepared by known methods.
  4-phenylpiperidine, 4-benzylpiperidine, 4-hydroxy-4-phenylpiperidine and 4-hydroxy-4-benzylpiperidine are commercially available.
  4-phenyl-1-wabicyclo [2.2.2] octane, or 4-phenylquinuclidine and 4-benzyl-1-azabicyclo [2.2.2] octane or 4-benzylquinuclidine are prepared according to T. Perrine, J. Org. Chem., 1957, 22 , 1484-1489.
  The compounds of formula (I) above also include those in which one or more atoms of hydrogen, carbon, fluorine or iodine have been replaced by their radioactive isotope for example tritium, carbon-14, fluor-19 or iodine 125. Such labeled compounds are useful in research, metabolism, pharmacokinetics or in biochemical tests as receptor ligands and can be used as pharmacological tools in humans or animals.
  The compounds according to the invention have been the subject of biochemical tests.
  The affinity of the compounds of formula (I) for the tachykinin receptors was evaluated in vitro by several biochemical tests using radioligands:
  • 1) The binding of [ ¹²⁵ I] BH-SP (P substance labeled with iodine 125 using the Bolton-Hunter reagent) to the NK ₁ receptors of human lymphoblastic cells.
  • 2) The [ ¹²⁵ I] His-NK _A binding to the NK ₂ receptors of the duodenum or of the rat bladder.
  • 3 °) [ ¹²⁵ I] His [MePhe ⁷ ] NK _B binding to the NK ₃ receptors of the rat cerebral cortex, of the guinea pig cerebral cortex and of the gerbil cerebral cortex as well as to the human NK ₃ clone receptors expressed by cells CHO (Buell et al., FEBS Letters, 1992, 299 , 90-95).
  
  The tests were carried out according to X. Emonds-Alt et al. (Eur. J. Pharmacol., 1993, 250 , 403-413).
  The compounds according to the invention strongly inhibit the binding to the NK ₁ receptors of IM9 human lymphoblastic cells. the inhibition constant Ki for lymphoblastic cell receptors is less than 5.10 ^-9 M. For the same compounds it has been found that the inhibition constant (Ki) for human cloned NK ₃ receptors is greater than or equal to 10 ^{- 7} M and that the inhibition constant (Ki) for the duodenum or rat bladder NK ₂ receptor is greater than or equal to 10 ^-7 M.
  The activity of the compounds according to the present invention as inhibitors of binding to NK ₁ receptors is clearly greater than that of neighboring compounds described in the prior art.
  Thus, the axial isomer of 1-methyl-1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5 iodide -yl] ethyl] -4-phenylpiperidinium has a Ki inhibition constant for substance P at the human lymphoblastic receptor of the order of 0.1.10 ^-9 M whereas 5- [2- (4-benzyl- 1-piperid-1-yl) ethyl] -5- (3,4-dichlorophenyl) -1-benzylpiperid-2-one described in application EP-0 512 901 in Example 1 (compound unsubstituted on benzyl) exhibits an inhibition constant Ki of the order of 10 ^-6 M measured under the same conditions.
  Similarly 4- (3,4-dichlorophenyl) -4- [2- (4-hydroxy-4-phenylpiperid-1-yl) ethyl] -1- [3,5-bis (trifluoromethyl) benzyl] pyrrolidin hydrochloride -2-one has an inhibition constant Ki of substance P at the human lymphoblastic receptor of the order of 0.1.10 ^-9 M while 1-benzyl-4- (3,4-dichlorophenyl) -4 hydrochloride - [2- (4-hydroxy-4-phenylpiperid-1-yl) ethyl] piperid-2-one described in application EP-0 512 901 in Example 3 has a Ki of the order of 10 ^-6 M measured under the same conditions.
  The compounds of the present invention are in particular active principles of pharmaceutical compositions, the toxicity of which is compatible with their use as medicaments.
  The compounds of formula (I) above can be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 50 mg / kg. In humans, the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment: prophylactic or curative .
  For their use as medicaments, the compounds of formula (I) are generally administered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
  Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I).
  In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredients can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants, forms subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.
  When preparing a solid composition in the form of tablets, the main active principle is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The sucrose tablets can be coated with various polymers, or other suitable materials, or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
  A preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
  A preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
  The water-dispersible powders or granules may contain the active principle in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or taste.
  Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
  For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
  For administration by inhalation, an aerosol is used containing for example sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant; one can also use a system comprising the active principle, alone or associated with an excipient, in powder form.
  The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
  In each dosage unit the active principle of formula (I) is present in the quantities adapted to the daily doses envisaged. In general each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 0.5 to 1000 mg of active ingredient, preferably 2.5 to 250 mg, to be administered one to four times a day.
  According to another of its aspects, the present invention relates to the use of the products of formula (I) for the preparation of medicaments intended to treat physiological disorders associated with an excess of tachykinins, in particular of Substance P and all Substance-P pathologies -dependent on the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous systems as well as pain and migraine.
  For example and without limitation:
  • acute and chronic pain related for example to migraine, pain of cancer and angina, chronic inflammatory processes such as osteoarthritis and rheumatoid arthritis,
  • inflammations such as chronic obstructive respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity for example to pollens and mites, rheumatoid arthritis, osteoarthritis, psoriasis, ulcerative colitis , Crohn's disease, inflammation of the intestines (irritable colon), prostatitis, neurological bladder, cystitis, urethritis, nephritis,
  • immune system diseases linked to the suppression or stimulation of immune cell functions, for example rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus,
  • diseases of the central nervous system of the neuropsychiatric or neurological type such as anxiety, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drugs- addiction, Down syndrome and Huntington's chorea as well as neurodegenerative diseases,
  • diseases of the gastrointestinal system such as nausea, vomiting, irritable colon, gastric and duodenal ulcers, diarrhea, hypersecretions,
  • diseases of the cardiovascular system such as hypertension, vascular aspects of migraine, edema, thrombosis, angina and vascular spasms,
  • heart rate and rhythm disorders, especially those caused by pain or stress.
  
  The present invention also includes a method for treating said conditions at the doses indicated above.
  In the Preparations and in the examples the following abbreviations are used:
  EtOH: ethanol
  MeOH: methanol
  Ether: diethyl ether
  Iso ether: diisopropyl ether
  DMF: dimethylformamide
  AcOEt: ethyl acetate
  DCM: dichloromethane
  THF: tetrahydrofuran
  NaOH: soda
  KHCO ₃ : potassium hydrogen carbonate
  NaHCO ₃ : sodium hydrogen carbonate
  NaCl: sodium chloride
  Triton B: 40% solution of N-benzyltrimethylammonium hydroxide in MeOH.
  Na ₂ SO ₄ : sodium sulfate
  MgSO ₄ : magnesium sulfate
  iPr: isopropyl
  RT: room temperature
  F: melting point
  NMR: nuclear magnetic resonance.
  s: singlet
  sd: split singlet
  d: doublet
  sept: septuplet
  m: massive
  mult: multiplet

PREPARATION 1 5- (3,4-Dichlorophenyl) -5- [2- (tetrahydropyran-2-yloxy) ethyl] piperid-2-one. A) 2- (3,4-Dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile.

20 g of 55-60% sodium hydride in oil are suspended in 200 ml of dry tetrahydrofuran. A solution of 85 g of 3,4-dichlorophenylacetonitrile in 500 ml of THF is added dropwise at 20 ° C over 30 minutes, then the reaction mixture is stirred at RT for 2 hours. The mixture is cooled to -20 ° C. and a solution of 98 g of 2- (2-bromoethoxy) tetrahydropyran in 100 ml of THF is added, the mixture is allowed to return to RT and after 2 hours a solution of 50 g is added of ammonium chloride in 3 liters of water. Extracted with 1.5 liters of ether, washed with a saturated solution of sodium chloride, decanted, dried over MgSO ₄ and concentrated in vacuo.

The residue is chromatographed on silica gel, eluent: dichloromethane. The pure product fractions are concentrated in vacuo to provide 83.6 g of an oil.

B) Ethyl 4-Cyano-4- (3,4-dichlorophenyl) -6- (tetrahydropyran-2-yloxy) hexanoate.

21 g of the nitrile previously prepared according to A) are dissolved in 100 ml of THF, then a solution of 0.067 mole of lithium diisopropylamide in 100 ml of THF is added dropwise and at ambient temperature and the reaction mixture is stirred for hour at TA. 12 g of ethyl 3-bromopropionate are then added and the mixture is heated at 50 ° C. for two hours. The mixture is cooled, poured into a saturated solution of ammonium chloride and extracted with ether, then washed with water, the ethereal phase is separated by decantation, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is purified by chromatography on silica gel, eluent: dichloromethane / ethyl acetate 100/1 (v / v). The concentration of the pure fractions provides 13 g of the expected compound.

C) 5- (3,4-Dichlorophenyl) -5- [2- (tetrahydropyran-2-yloxy) ethyl] piperid-2-one.

13 g of the compound prepared above are dissolved in 250 ml of ethanol and 40 ml of ammonia and are hydrogenated at room temperature and atmospheric pressure in the presence of Raney® nickel. When the theoretical volume of hydrogen is absorbed, the mixture is filtered on Celite® and the filtrate is concentrated under vacuum. The residue is taken up in water, extracted with ether, then the ethereal phase is washed with water, dried over MgSO ₄ and concentrated in vacuo to obtain 9 g of the expected product.

PREPARATION 2. 5- [2- (Tetrahydropyran-2-yloxy) ethyl] -5- (3,4-difluorophenyl) piperid-2-one. A) 2- (3,4-Difluorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile.

14.4 g of 60% sodium hydride in oil are suspended in 250 ml of THF and cooled in a water bath. A solution of 50 g of 3,4-difluorophenylacetonitrile in 50 ml of THF is added dropwise, then the mixture is left at RT for 3 hours and a solution of 68.16 g of 2- (2-bromoethoxy) tetrahydropyran is added dropwise in 100 ml of THF. After one night at RT, acidified with a pH2 buffer, the THF is evaporated, taken up in water and extracted with ether. Wash 2 times with a pH4 buffer solution, then wash with water and with a saturated solution of sodium chloride. Decanted, dried the organic phase on MgSO ₄ and concentrated under vacuum. The residue is chromatographed on silica eluting with pure toluene then containing up to 3% AcOEt. 49.5 g of the expected product are obtained.

B) Methyl 6- (Tetrahydropyran-2-yloxy) -4- (3,4-difluorophenyl) -4-cyanohexanoate.

The product obtained in the previous step (28.12 g) is placed in 100 ml of THF, 1 ml of Triton B is added and the mixture is heated to reflux and then 9.46 g of methyl acrylate are added dropwise. The mixture is left to return to RT, the solvent is evaporated, taken up in water and extracted with ether. Wash twice with water, twice with a pH4 buffer solution, with water and then with a saturated solution of sodium chloride. Decanted, dried the organic phase over MgSO ₄ and concentrated in vacuo to obtain 34.6 g of the expected product.

C) 5- [2- (Tetrahydropyran-2-yloxy) ethyl] -5- (3,4-difluorophenyl) piperid-2-one.

The product (34.6 g) obtained in the previous step is dissolved in 500 ml of EtOH 95. 5 g of solid KHCO _{3 are added,} then Raney® nickel. Hydrogenation is carried out at 60 ° C. under 20.4 bars. After 4 hours, filter through Celite® and evaporate the solvent. It is taken up in water, extracted with AcOEt, washed twice with water and with a saturated solution of sodium chloride. The organic phase is dried over MgSO ₄ and concentrated in vacuo. 32 g of the expected product are obtained.

PREPARATION 3. 6- (3,4-Dichlorophenyl) -6- [2- (tetrahydropyran-2-yloxy) ethyl] perhydroazepin-2-one. A) ethyl 5-Cyano-5- (3,4-dichlorophenyl) pentanoate.

5.9 g of 55% sodium hydride in oil are suspended in 50 ml of THF; cooled in an ice bath and 25 g of 3,4-dichlorophenylacetonitrile in 25 ml of THF are added dropwise; again cooled in an ice bath and 26.21 g of ethyl 4-bromobutanoate dissolved in 25 ml of THF are added dropwise. After one night at RT, evaporated to dryness and then taken up in a 2N hydrochloric acid solution and extracted with ether. Washing is carried out with a 2N hydrochloric acid solution and then with a saturated sodium chloride solution. The organic phase is dried over MgSO ₄ then concentrated under vacuum and the residue is chromatographed on silica eluting with pure toluene until a toluene / AcOEt mixture (100/3; v / v). 17 g of the expected product are obtained.

B) Ethyl 5-Cyano-5- (3,4-dichlorophenyl) -7- (tetrahydropyran-2-yloxy) heptanoate.

2.5 g of 55% sodium hydride in oil are suspended in 50 ml of DMF, the mixture is cooled to -20 ° C. and a mixture of 11.8 g of 2- ( 2-bromoethoxy) tetrahydropyran and 17 g of the compound obtained in the previous step in 50 ml of DMF. After overnight at RT, evaporated to dryness, taken up in a pH4 buffer solution and then extracted with AcOEt. Washing is carried out with a pH4 buffer solution, washing with water and then with a saturated solution of sodium chloride. The organic phase is dried over MgSO ₄ then concentrated and the residue is chromatographed on silica, eluting with pure toluene until a toluene / AcOEt mixture (100/10; v / v). 15.4 g of the expected product are obtained.

C) ethyl 5- (Aminomethyl) -5- (3,4-dichlorophenyl) -7- (tetrahydropyran-2-yloxy) heptanoate.

The product obtained in the previous step (15.4 g) is dissolved in 200 ml of MeOH, 25 ml of a saturated solution of ammonia in MeOH are added, then hydrogenation is carried out at 40 ° C under atmospheric pressure. presence of Raney® nickel. The catalyst is filtered, evaporated to dryness and the residue is taken up in ether. Washed with water, with a saturated solution of sodium chloride, dried over MgSO ₄ and concentrated in vacuo to obtain 12.8 g of the expected product.

D) 6- (3,4-Dichlorophenyl) -6- [2- (tetrahydropyran-2-yloxy) ethyl] perhydroazepin-2-one.

The product obtained in the previous step (12.8 g) is dissolved in 200 ml of xylene and heated at reflux for 48 hours. Evaporated to dryness and then the residue is chromatographed on silica, eluting with pure DCM until a DCM / MeOH mixture (98/2; v / v). 10.1 g of the expected product are obtained.

PREPARATION 4 4- (3,4-Dichlorophenyl) -4- [2- (tetrahydropyran-2-yloxy) ethyl] pyrrolidin-2-one. A) 2- (3,4-Dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile.

This compound is prepared in Preparation 1, step A.

B) Ethyl 3-Cyano-3- (3,4-dichlorophenyl) -5- (tetrahydropyran-2-yloxy) pentanoate.

57 g of the compound from step A are dissolved in 150 ml of DMF. 7.85 g of 55% sodium hydride in oil are added in small portions. After 1 hour of heating to 60 ° C., the mixture is cooled to RT and 30.8 g of ethyl bromoacetate in 50 ml of DMF are added dropwise. After 2 hours with stirring at RT, the DMF is evaporated under reduced pressure, extracted with ether and then washed with water until neutral pH. After drying over MgSO ₄ and evaporation of the solvents, the residue is chromatographed on silica, eluting with a DCM / AcOEt mixture (95/5; v / v). 29 g of the expected compound are obtained.

C) 4- (3,4-Dichlorophenyl) -4- [2- (tetrahydropyran-2-yloxy) ethyl] pyrrolidin-2-one.

Hydrogenation is carried out at atmospheric pressure and TA 8 g of the compound obtained in step B in solution in 100 ml of EtOH 100, 5 ml of water and 0.6 g of NaHCO ₃ . The catalyst is filtered and the filtrate is evaporated under vacuum. The residue is extracted with DCM, washed with water, dried over MgSO ₄ and the solvent is evaporated under vacuum. 6 g of the expected product are obtained.

PREPARATION 4 BIS 4- (3,4-Dichlorophenyl) -4- [2- (tetrahydropyran-2-yloxy) ethyl] pyrrolidin-2-one. A) Diethyl 3-Cyano-3- (3,4-dichlorophenyl) -1,5-pentanedioate.

To 10 g of 3,4-dichlorophenylacetonitrile dissolved in 50 ml of THF, 4.3 g of 60% sodium hydride in oil is added and the mixture is stirred until the evolution of hydrogen is complete. . The mixture is cooled to 0 ° C. and 18 g of ethyl bromoacetate dissolved in 50 ml of THF are added dropwise. It is left to return to RT and left to stir overnight. Evaporated to dryness, taken up in ether, washed with a buffer solution at pH = 2 and dried over MgSO ₄ . The residue is chromatographed on silica, eluting with a DCM / AcOEt mixture (80/20; v / v). 15 g of the expected compound are obtained.

B) 4- (3,4-dichlorophenyl) -4- (ethoxycarbonylmethyl) pyrrolidin-2-one.

15 g of the compound obtained in the previous step are dissolved in 100 ml of ethanol and hydrogenated at AT and at atmospheric pressure in the presence of Raney® nickel. When the theoretical volume of hydrogen to be consumed is reached, the catalyst is filtered, evaporated to dryness, taken up in ether, washed with water and dried over MgSO ₄ . 12 g of the expected compound are obtained.

C) 4- (3,4-dichlorophenyl) -4- (2-hydroxyethyl) pyrrolidin-2-one.

12 g of the product obtained in the previous step and 6 g of calcium borohydride are dissolved in 50 ml of THF. After 2 hours with stirring at 0 ° C., the mixture is allowed to return to RT then the reaction medium is poured onto water and acidified to pH 1 by addition of a concentrated solution of hydrochloric acid. Extraction is carried out with ethyl acetate, washing with water and drying over MgSO ₄ . The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100/5; v / v). 10 g of the expected compound are obtained.

D) 4- (3,4-Dichlorophenyl) -4- [2- (tetrahydropyran-2-yloxy) ethyl] pyrrolidin-2-one.

To 10 g of the product obtained in the previous step, dissolved in 50 ml of DCM with 0.1 g of paratoluenesulfonic acid, 3 g of 3,4-dihydro-2H-pyrane are added dropwise at 0 ° C in solution in 10 ml of THF. Then left overnight at RT, evaporated to dryness, taken up in ether, washed with water, with a saturated NaHCO ₃ solution and dried over MgSO ₄ . The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100/5; v / v). 12 g of the expected compound are obtained.

PREPARATION 5 5- (3,4-Dichlorophenyl) -5- [3- (tetrahydropyran-2-yloxy) propyl] piperid-2-one. A) 2- (3,4-Dichlorophenyl) -5- (tetrahydropyran-2-yloxy) pentanenitrile.

To a solution of 13.35 g of 3,4-dichlorophenylacetonitrile in 100 ml of THF, 2.8 g of 60% sodium hydride in oil are added at RT and in small portions and the mixture is left stirring for 3 hours. at TA. The reaction mixture is cooled to -20 ° C., a solution of 16 g of 2- (3-bromopropoxy) tetrahydropyran in 30 ml of THF is added dropwise and the mixture is left stirring for 3 hours while allowing the temperature to rise to RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a buffer solution pH = 4, with water, dried over MgSO ₄ and the solvent is evaporated under vacuum. The residue is chromatographed on silica, eluting with a toluene / AcOEt mixture (100/3; v / v). 11 g of the expected product are obtained.

B) Ethyl 4-Cyano-4- (3,4-dichlorophenyl) -7- (tetrahydropyran-2-yloxy) heptanoate.

To a solution of 11 g of the compound obtained in the preceding step and 1 ml of Triton B in 25 ml of dioxane, 3.3 g of ethyl acrylate is added at RT and drop by drop, then the mixture is left stirring for 1 hour at YOUR. The reaction mixture is diluted by adding 200 ml of ether, the organic phase is washed four times with water, with a saturated solution of sodium chloride, dried over MgSO ₄ and the solvent is evaporated under vacuum. 11 g of the expected product are obtained.

C) 5- (3,4-Dichlorophenyl) -5- [3- (tetrahydropyran-2-yloxy) propyl] piperid-2-one.

A mixture of 11 g of the compound obtained in the preceding step, 1 g of Raney® nickel and 0.77 g of NaHCO ₃ in 120 ml of EtOH 95 is hydrogenated at 40 ° C. and at 10.2 bars. filters the catalyst on Celite® and concentrates the filtrate under vacuum. The residue is extracted with DCM, the organic phase is washed with water and with saturated sodium chloride solution, dried over MgSO ₄ and the solvent is evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (97/3; v / v). 6.8 g of the expected product are obtained.

EXAMPLE 1 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] ethyl] -4-phenylquinuclidinium chloride, monohydrate.

m = 2; n = 1 ;

A^⊖ = Cl^⊖

m = 2; n = 1;

A ^⊖ = Cl ^⊖

A) 5- (2-Hydroxethyl) -5- (3,4-dichorophenyl) -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

One hour stirred at RT, 1.86 g of the compound obtained in PREPARATION 1 and 0.61 g of potassium tert- butoxide in 30 ml of THF; 1.54 g of 3,5-bis (trifluoromethyl) benzyl bromide are added and the mixture is heated at 50 ° C. for 2 hours. The reaction medium is evaporated to dryness. The residue is taken up in 25 ml of methanol, cooled to 0 ° C., hydrochloric ether is added to pH = 1 and then evaporated to dryness. The residue obtained is taken up in ethyl acetate, washed 3 times with water, dried over MgSO ₄ , the solvent is evaporated under vacuum and 2.6 g of the expected product are obtained.

B) 5- (2-Mesyloxyethyl) -5- (3,4-dichlorophenyl) -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

A mixture of the product obtained in the previous step (2.6 g) and 0.66 g of triethylamine in 30 ml of DCM is cooled to 0 ° C. Then 0.63 g of methanesulfonyl chloride is added in 10 ml of DCM. After 15 minutes, evaporated to dryness then extracted with ether, washed with water and then with saturated sodium chloride solution, dried over MgSO ₄ , the solvent evaporated under vacuum and 2.95 g is obtained of the expected product.

C) 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] ethyl] -4-phenylquinuclidinium chloride, monohydrate .

A mixture containing the mesylate obtained in the previous step (2.95 g) and 1.41 g of 4-phenylquinuclidine in 1.2 ml of DMF is heated at 80 ° C. for 3 hours. After evaporation to dryness, the residue is taken up in DCM and then washed twice with a 2N hydrochloric acid solution and then with water. It is dried over MgSO ₄ , concentrated under vacuum and then chromatographed on silica, eluting with a DCM / MeOH mixture (95/5; v / v). 0.64 g of the expected product is obtained after crystallization from pentane, mp 158-160 ° C.

EXAMPLE 2 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-difluorophenyl) 2-oxopiperid-5-yl] ethyl] -4-phenylquinuclidinium chloride dihydrate.

m = 2 ; n = 1;

A^⊖ = Cl^⊖

m = 2; n = 1;

A ^⊖ = Cl ^⊖

A) 5- (3,4-Difluorophenyl) -5- [2- (tetrahydropyran-2-yloxy) ethyl] -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

5 g of the compound obtained in PREPARATION 2 are dissolved in 90 ml of THF, 1.89 g of potassium tert- butoxide is added and the mixture is left at RT for one hour. Then a solution of 4.75 g of 3,5-bis (trifluoromethyl) benzyl bromide in 30 ml of THF is added dropwise and the mixture is left stirring at RT overnight. It is evaporated, taken up in water, extracted with AcOEt and then washed twice with water then with a saturated solution of sodium chloride, dried over MgSO ₄ and the solvent evaporated under vacuum. 8.4 g of the expected product are obtained.

B) 5- (3,4-Difluorophenyl) -5- (2-hydroxyethyl) -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

The product obtained in the preceding step (8.4 g) is dissolved in 70 ml of methanol and a solution of hydrochloric ether is added until a pH below 1 is obtained. After 15 minutes, the product is evaporated. , takes up the residue in a saturated solution of HCl gas in MeOH and concentrates the solvent under vacuum. The residue is taken up in DCM and washed with a 5% NaHCO ₃ solution and then with a saturated sodium chloride solution, dried over MgSO ₄ and the solvent evaporated under vacuum. 5.1 g of the expected product are obtained, which crystallizes from ether. M = 120 ° C.

C) 5- (3,4-Difluorophenyl) -5- (2-methanesulfonyloxyethyl) -1- [3,5-bis (trifluoro methyl) benzyl] piperid-2-one.

A solution of 4 g of the compound obtained in the preceding step in 50 ml of DCM is prepared, 1 g of triethylamine is added, then it is cooled in an ice bath and 1.04 g of methanesulfonyl chloride are added dropwise in 20 ml of DCM. Evaporated, taken up in water and extracted with AcOEt, then washed successively with water, a 2N HCl solution, water, a 5% NaHCO ₃ solution, water, a saturated solution of sodium chloride. It is dried over MgSO ₄ and the solvent is evaporated under vacuum. 4.7 g of the expected product are obtained.

D) 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-difluorophenyl) 2-oxopiperid-5-yl] ethyl] -4-phenylquinuclidinium chloride dihydrate.

0.60 g of 4-phenylquinuclidine and 1.5 g of the product obtained in the preceding step are mixed in the minimum of DMF and the mixture is heated at 100 ° C. for 3 hours. We leaves to return to RT, evaporates, resumes with DCM then washed successively with water, a 2N HCl solution (3 times), water, a saturated solution of sodium chloride, dried over MgSO ₄ and evaporated under vacuum the solvent. 1 g of the expected product is obtained after trituration in ether, then wringing. Mp 125 ° C.

EXAMPLE 3 1- [2- [1- [3,5-bis (trifluoromethyl) brnzyl] -6- (3,4-dichlorophenyl) -2-oxoperhydroazepin-6-yl] ethyl] -4-phenylquinuclidinium chloride, monohydrate.

m=2; n=2;

A^⊖ = Cl^⊖

m = 2; n = 2;

A ^⊖ = Cl ^⊖

A) 6- (3,4-Dichlorophenyl) -6- [2- (tetrahydropyran-2-yl) ethyl] -1- [3,5-bis (trifluoromethyl) benzyl] perhydroazepin-2-one.

1 g of the compound obtained in PREPARATION 3 is dissolved in 15 ml of THF, 0.33 g of potassium tert- butoxide is added and the mixture is left at RT for 1 hour and then 0.71 g of chloride is added dropwise of 3,5-bis (trifluoromethyl) benzyl in 5 ml of THF. After 2 hours, the mixture is evaporated, taken up in water and extracted with AcOEt, then washed with water and a saturated solution of sodium chloride. It is dried over MgSO ₄ and the solvent is evaporated under vacuum. 1.5 g of the expected product are obtained.

B) 6- (3,4-Dichlorophenyl) -6- (2-hydroxyethyl) 1- [3,5-bis (trifluoro methyl) benzyl] perhydroazepin-2-one.

1.5 g of the product obtained in the previous step are dissolved in 20 ml of methanol, hydrochloric ether is added until a pH below 1 is reached. After 15 minutes, the mixture is evaporated and taken up twice. hydrochloric methanol and evaporated to dryness to obtain 1.4 g of the expected product.

C) 6- (3,4-Dichlorophenyl) -6- (2-methanesulfonyloxyethyl) -1- [3,5-bis (trifluoromethyl) benzyl] perhydroazepin-2-one.

1.4 g of the product obtained in the preceding step are dissolved in 15 ml of DCM, 0.32 g of triethylamine is added and the medium is cooled by an ice bath. 0.33 g of methanesulfonyl chloride is added dropwise in 5 ml of DCM and let return to TA. Evaporated, taken up in water and extracted with AcOEt, then washed with water and with a saturated solution of sodium chloride. It is dried over MgSO ₄ , the solvent is evaporated, then chromatography on silica eluting with DCM and then a DCM / MeOH mixture (99/1; v / v). 1.3 g of the expected product are obtained.

D) 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -6- (3,4-dichlorophenyl) -2-oxoperhydroazepin-6-yl] ethyl] -4-phenylquinuclidinium chloride, monohydrate .

0.48 g of 4-phenylquinuclidine and 1.3 g of the product obtained in the preceding step are mixed in a minimum of DMF and the mixture is heated at 100 ° C. for 5 hours. Then 0.63 g of sodium iodide is added and the heating is maintained for 1 hour. The mixture is allowed to return to AT, the solvent is evaporated and then taken up in water and extracted with DCM. Washed with water, with a saturated solution of sodium chloride, dried over MgSO ₄ and the solvent evaporated. It is taken up in ethanol and then the medium is passed over an IRA68 hydrochloric resin. Evaporated, taken up in DCM and washed 3 times with water, 2 times with a 2N HCl solution, again 2 times with water and then with a saturated solution of sodium chloride. It is dried over MgSO ₄ and the solvent is evaporated. The expected product is triturated in ether and then drained; 0.8 g is obtained, mp = 157 ° C.

By proceeding as in EXAMPLE 1, the compounds described in Table 1 below were also prepared.

EXAMPLES 7 and 8

1-methyl-1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] ethyl] -4-phenylpiperidinium iodide (axial isomer and equatorial isomer).

EXAMPLE 7 (I):

R₁ = Me en position axiale ;

n = 1 ;

A^⊖ = I ^⊖ ; m = 2

R ₁ = Me in axial position;

n = 1;

A ^⊖ = I ^⊖ ; m = 2

EXAMPLE 8 (I):

R₁ = Me en position équatoriale ;

n = 1 ;

A ^⊖ = I^⊖ ; m = 2

R ₁ = Me in equatorial position;

n = 1;

A ^⊖ = I ^⊖ ; m = 2

A) 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] ethyl] -4-phenylpiperidine hydrochloride.

2.79 g of 5- (2-mesyloxyethyl) -5- (3,4-dichlorophenyl) -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one prepared in Example 1 are mixed, step B, 1.95 g of K ₂ CO ₃ and 0.91 g of 4-phenylpiperidine in 6 ml of acetonitrile and 6 ml of DMF and the mixture is heated at 80 ° C. for 4 hours. After evaporation of the solvents, extraction is carried out with ethyl acetate, washing with water and then with a saturated NaCl solution. It is dried over MgSO ₄ , concentrated and then chromatographed on silica, eluting with DCM / MeOH (100/1; v / v). A sample of the product obtained is taken up in a hydrochloric ether solution and the solvent is evaporated. 0.365 g of the expected product is obtained, which crystallizes from a pentane / ether mixture, mp = 170 ° C.

B) 1-methyl-1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] ethyl] iodide - 4-phenylpiperidinium (axial isomer and equatorial isomer).

A mixture comprising 1.1 g of the compound prepared in the preceding step in the form of a base in 10 ml of iodide is left stirring for 18 hours at RT. methyl. Evaporate the excess methyl iodide, take up in ether, filter, then take up in DCM and evaporate. The residue is chromatographed on silica. By eluting with a DCM-MeOH mixture (100/3; v / v), the least polar compound is obtained in which the methyl is in the axial position on the nitrogen of the piperidine, M = 128 ° C. By eluting with a DCM-MeOH mixture (100/15; v / v), the most polar compound is obtained on which the methyl is in the equatorial position on the nitrogen of the piperidine, M = 166 ° C.

EXAMPLE 9 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -4- (3,4-dichlorophenyl) -2-oxopyrrolidin-4-yl] ethyl] -4-phenylquinuclidinium chloride dihydrate.

m=2; n = 0 ;

A^⊖ = Cl^⊖

m = 2; n = 0;

A ^⊖ = Cl ^⊖

A) 4- (3,4-Dichlorophenyl) -1- [3,5-bis (trifluoromethyl) benzyl] -4- [2- (tetrahydropyran-2-yloxy) ethyl] pyrrolidin-2-one.

A mixture containing 3 g of the compound obtained in Preparation 4 and 0.959 g of potassium tert- butoxide in 80 ml of THF is stirred for 1 hour at RT, then 2.24 g of 3.5-bis chloride ( trifluoromethyl) benzyl and heated to 50 ° C for 3 hours. Cooled to RT, the solvents are evaporated and then extracted with AcOEt, washed with water, with a saturated solution of sodium chloride. The organic phase is dried over MgSO ₄ then concentrated and the residue is chromatographed on silica eluting with DCM / MeOH (100/1; v / v). 2.3 g of the expected product are obtained.

B) 4- (3,4-Dichlorophenyl) -1- [3,5-bis (trifluoromethyl) benzyl] -4- [2- (mesyloxy) ethyl] pyrrolidin-2-one.

2.3 g of the compound obtained in the preceding step are dissolved in 100 ml of methanol and hydrochloric ether is added to a pH below 1. It is stirred for 15 minutes, evaporated, taken up in AcOEt, washed with water then with a saturated solution of sodium chloride. It is dried over Na ₂ SO ₄ and evaporated. 2 g of the alcohol thus obtained are placed in 50 ml of DCM in the presence of 0.61 g of triethylamine and a solution containing 0.51 g of methanesulfonyl chloride and 10 ml of DCM is added dropwise cold then stirred at RT for 15 minutes. The reaction medium is evaporated, extracted with AcOEt, washed with water, then with a saturated solution of sodium chloride. After drying over Na ₂ SO ₄ and evaporation of the solvent, 2 g of the expected product are obtained.

C) 1- [2- [1- [3,5-bis (trifluoromethyl) benzyl] -4- (3,4-dichlorophenyl) -2-oxopyrrolidin-4-yl] ethyl] -4-phenylquinuclidinium chloride dihydrate .

A mixture containing 1.12 g of the compound obtained in the preceding step and 0.544 g of 4-phenylquinuclidine in 2 ml of DMF is heated at 80 ° C. for 4 hours. Cool to RT then add ice and water. The reaction medium is extracted with DCM and then washed 6 times with 2N HCl, then with water and with a saturated solution of sodium chloride. It is dried over Na ₂ SO ₄ and the solvent is evaporated under vacuum. 0.78 g of the expected product is obtained, mp = 120-122 ° C.

EXAMPLE 10 4- (3,4-dichlorophenyl) -4- [2- (4-hydroxy-4-phenylpiperid-1-yl) ethyl] -1- [3,5-bis (trifluoromethyl) benzyl] pyrrolidin-2- hydrochloride one.

n = 0 ;

m = 2

n = 0;

m = 2

A mixture containing 1 g of 4- (3,4-dichlorophenyl) -1- [3,5-bis (trifluoromethyl) benzy] -4- [2- (mesyloxy) ethyl] pyrrolidin-2 is prepared in 2 ml of DMF one obtained in Example 9, step B, 0.875 g of 4-hydroxy-4-phenylpiperidine and 0.483 g of potassium carbonate and the mixture is heated at 80 ° C. for 3 hours. The mixture is allowed to cool and then ice, water and ethyl acetate are added. Extraction is carried out with AcOEt, washing with water and then with a sodium chloride solution. The pure product is obtained by chromatography on silica, eluting with a DCM-MeOH mixture (100/3; v / v). The hydrochloride is then prepared by the action of hydrochloric acid in DCM. The expected product crystallizes from a pentane-ether mixture, m = 0.555 g, F = 136-138C.

EXAMPLE 11 4- (3,4-Dichlorophenyl) -4- [2- (4-phenylpiperid-1-yl) ethyl] -1- [3,5-bis (trifluoromethyl) benzyl] pyrrolidin-2-one hydrochloride, hemihydrate.

n= 0 ;

m = 2

n = 0;

m = 2

A mixture of 2 g of the compound obtained in step B of EXAMPLE 9, 0.67 g of 4-phenylpiperidine, 1.43 g of potassium carbonate in 6 ml of is heated at 80 ° C. for 4 hours. acetonitrile and 6 ml of DMF. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed three times with water and with saturated sodium chloride solution, dried over Na ₂ SO ₄ and the solvent is evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture from (100/1; v / v) to (100/3; v / v). the product obtained is dissolved in DCM, acidified to pH = 1 by adding a saturated solution of HCl gas in ether and concentrated in vacuo. 0.39 g of the expected product is obtained after crystallization from pentane, mp 126-130 ° C.

EXAMPLE 12 1- [3- [1- [3,5-bis (trifluoromethyl) bcnzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] propyl] -4-phenylquinuclidinium chloride.

m = 3 ; n = 1 ;

A^⊖ = Cl ^⊖

m = 3; n = 1;

A ^⊖ = Cl ^⊖

A) 5- (3,4-Dichlorophenyl) -5- [3- (tetrahydropyran-2-yloxy) propyl] -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

To a solution of 6.8 g of the compound obtained in PREPARATION 5 in 100 ml of THF, 1.98 g of potassium tert- butoxide is added and the mixture is left stirring for 1 hour at RT. Then 4.62 g of 3,5-bis (trifluoromethyl) benzyl chloride is added and the reaction mixture is heated at 50 ° C. for 2 hours. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with a saturated NaCl solution, dried over MgSO ₄ and the solvent is evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100/1; v / v). 10 g of the expected product are obtained.

B) 5- (3,4-Dichlorophenyl) 5- (3-hydroxypropyl) -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

To a solution of 10 g of the compound obtained in the preceding step in 150 ml of MeOH, a saturated solution of HCl gas in ether is added until pH <1 and the mixture is left stirring for 10 minutes at RT. It is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, with a 5% NaHCO ₃ solution, with a saturated NaCl solution, dried over MgSO ₄ and the solvent evaporated under vacuum. 8.8 g of the expected product are obtained in the form of an oil.

C) 5- (3,4-Dichlorophenyl) -5- [3- (methanesulfonyloxy) propyl] -1- [3,5-bis (trifluoromethyl) benzyl] piperid-2-one.

A solution of 8.8 g of the compound obtained in the preceding step and 2.51 g of triethylamine in 100 ml of DCM is cooled in an ice bath, a solution of 2.09 g of methanesulfonyl chloride in dropwise added 20 ml of DCM and leaves for 10 minutes with stirring. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with a saturated NaCl solution, dried over MgSO ₄ and the solvent is evaporated under vacuum. 8.5 g of the expected product are obtained.

D) 1- [3- [1- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -2-oxopiperid-5-yl] propyl] -4-phenylquinuclidinium chloride.

A mixture of 2.41 g of the compound obtained in the preceding step and 0.996 g of 4-phenylquinuclidine in 4 ml of DMF is heated at 80 ° C. for 4 hours. After cooling to RT, the reaction mixture is poured into a water / ice mixture, extracted with DCM, the organic phase is washed with water, four times with a 2N HCl solution, three times with a saturated NaCl solution, dry on MgSO ₄ and evaporate the solvent under vacuum. 1.45 g of the expected product are obtained after trituration in the pentane / ether mixture and then wringing, M = 132-134 ° C.

Claims (10)

A compound of formula:

in which : - m is two or three; - n is 0, 1 or 2; - Am represents a group chosen from: at)

b)

and when n = 0, Am can also represent the group: vs)

- R ₁ represents a (C ₁ -C ₄ ) alkyl or a benzyl; - R ₂ represents a phenyl which is unsubstituted or substituted one or more times with a halogen atom, a hydroxyl, a (C ₁ -C ₄ ) alkoxy, a (C ₁ -C ₄ ) alkyl, a trifluoromethyl, said substituents being identical or different; - X represents a hydrogen atom or a hydroxyl group; - x is zero or one; - Ar represents a phenyl which is unsubstituted or substituted one or more times by a halogen atom; naphthyl or indolyl; - Z represents a phenyl substituted one or more times by a halogen atom, a (C ₁ -C ₄ ) alkyl, a trifluoromethyl; - A ^⊖ represents an anion; and its possible salts with mineral or organic acids and its possible solvates. A compound of formula (I) according to claim 1 wherein m = 2; A compound of formula (I) according to claim 1 in which Z represents a group chosen from dimethylphenyl, trifluoromethylphenyl and bistrifluoromethylphenyl. A compound according to claim 1 of formula (I) in which: - Ar represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl; - Z represents 3,5-dimethylphenyl, 3,5-bis (trifluoromethyl) phenyl or 2,4-bis (trifluoromethyl) phenyl; and - either n = 0, 1 or 2 and Am represents a group a) or b) as defined in claim 1, or n = 0 and Am represents a group c) as defined in claim 1; - A ^⊖ represents a pharmaceutically acceptable anion. A compound according to claim 1 of formula:

in which Am _a represents group b) as defined for (I) in claim 1 and n, m, Ar and Z are as defined for (I) in claim 1
and its possible solvates. A pharmaceutically acceptable salt of a compound of formula:

where a is 0 or 1 and A ^⊖ is a pharmaceutically acceptable anion and its possible solvates. A process for the preparation of the compounds of formula (I) according to claim 1 characterized in that: 1) a compound of formula is treated:

wherein m, n and Ar are as defined for (I) in claim 1 and E represents an O-protecting group such as tetrahydropyran-2-yl, benzoyl or a C ₁ -C ₄ acyl;
with a halogenated derivative of formula:

Hal-CH ₂ -Z (III)

wherein Z is as defined for (I) in claim 1 and Hal represents a halogen atom, preferably bromine or chlorine; 2) the O-protecting group is transformed into a hydroxyl group by the action of an acid or a base; 3) the alcohol thus obtained is treated with the formula:

wherein m, Ar, Z and n are as defined for (I) in claim 1;
with methanesulfonyl chloride, benzenesulfonyl chloride, paratoluenesulfonyl chloride or trifluoromethanesulfonyl chloride; 4) reacting the compound thus obtained of formula:

wherein R represents a methyl, phenyl, paratolyl or trifluoromethyl group;
with a secondary or tertiary amine AmH or Am; 5) the product thus obtained is isolated and, optionally, the sulfonate anion of the quaternary salt is exchanged with another anion and, optionally, the product obtained is converted into one of its salts. Pharmaceutical composition containing, as active principle, a compound according to any one of Claims 1 to 6 or one of their pharmaceutically acceptable salts. Pharmaceutical composition according to claim 8, in the form of a dosage unit, in which the active principle is mixed with at least one pharmaceutical excipient. Pharmaceutical composition according to claim 9, containing from 0.5 to 1000 mg of active principle.